The merger of decatungstate and copper catalysis to enable aliphatic C( sp 3 )–H trifluoromethylation

The introduction of a trifluoromethyl (CF 3 ) group can dramatically improve a compound’s biological properties. Despite the well-established importance of trifluoromethylated compounds, general methods for the trifluoromethylation of alkyl C–H bonds remain elusive. Here we report the development of a dual-catalytic C( sp 3 )–H trifluoromethylation through the merger of light-driven, decatungstate-catalysed hydrogen atom transfer and copper catalysis. This metallaphotoredox methodology enables the direct conversion of both strong aliphatic and benzylic C–H bonds into the corresponding C( sp 3 )–CF 3 products in a single step using a bench-stable, commercially available trifluoromethylation reagent. The reaction requires only a single equivalent of substrate and proceeds with excellent selectivity for positions distal to unprotected amines. To demonstrate the utility of this new methodology for late-stage functionalization, we have directly derivatized a broad range of approved drugs and natural products to generate valuable trifluoromethylated analogues. Preliminary mechanistic experiments reveal that a ‘Cu–CF 3 ’ species is formed during this process and the critical C( sp 3 )–CF 3 bond-forming step involves the copper catalyst.